So concluded the paper published by Rongwang Yang and colleagues [1] looking at blood levels of various trace elements including "zinc (Zn), copper (Cu), iron (Fe), magnesium (Mg), and lead (Pb)" in a group of children diagnosed with ADHD compared to a group of non-ADHD controls.

Based on their analysis of blood samples using atomic absorption spectrometry, researchers observed that many of the metals (trace elements) analysed were not greatly different between their groups. Lower levels of zinc however, and "the number out of normal ranges" in relation to zinc were noted. Further: "Zinc levels were negatively correlated with parent-rated scores of inattentive subscale of SNAP-IV (r = − 0.40) as well as with total score of SNAP-IV (r = − 0.24)" where the SNAP-IV refers to the Swanson, Nolan, and Pelham – IV questionnaire, a tool used to screen/assess for possible ADHD.

This is not the first time that zinc and ADHD have been talked about in the same breath (see here). Outside of linking levels of zinc to ADHD - or diagnostic facets of ADHD - one is also presented with other research suggestive that supplementation 'for ADHD' including zinc *might* show some effect (see here). There is the other question of whether zinc alone or in conjunction with other elements and/or biological factors might be important to the presentation of ADHD [2] but this is perhaps another reason why this area is deserving of further investigation. Indeed, further study of the possible processes through which zinc might influence the presentation of ADHD is also required.

And given that ADHD is something not exactly under-represented when it comes to other labels (see here), one has to question what role this fact might play in a more complicated clinical picture with zinc in mind (see here)?

The details? "The patient was a healthy girl" ('was' being the operative word). Some time before she was 2 years of age, she experienced some really quite sudden and stark behavioural changes "manifesting as bouts of irritability, aggression, inconsolable crying, and self-mutilatory behavior (self-biting)." A fever brought about various other somatic symptoms, as eye contact was lost and insomnia set in. "In addition, she developed a progressive regression in gross and fine motor skills and an inability to swallow" with seizures following. Things were getting really serious.

Various tests were carried out which in the most part came up within typical reference ranges (including a "brain MRI"). Someone had their suspicions that NMDA receptor encephalitis *might* fit with the presented profile. Lo and behold, following testing a positive result was received albeit "one month later" (samples had to be sent out of country for analysis). Interventions were put in place ("intravenous immunoglobulin (IVIg) and intravenous methylprednisolone... plasma exchange... rituximab") with some being more successful than others. Of particular note: "A dramatic improvement in her social skills and irritability appeared within hours following plasma exchange." Interesting. Things did eventually improve for the young girl at the centre of the Khundakji paper as we are told that: "Apart from mild speech delay, her neurological exam and developmental milestones are normal."

What lessons can be learned from such case reports? How about starting with the idea that rapid onset childhood regression that includes 'autistic features' should always be investigated as a sign of unmet medical need such as a response to infection (see here)? Perhaps also acknowledge that the presentation of autism or autistic features is not a life-long, immutable, set-in-stone scenario for some people (see here and see here and see here)? And as for the effects of plasmapheresis (plasma exchange) on this particular young child linked to a "dramatic improvement in her social skills and irritability", I'm wondering whether there is a research study or two to be designed and conducted on this topic (with due care)?

What was different about the Sourander results compared with some of the other studies in this area was their focus on the measurement of cotinine levels - cotinine being a biomarker for exposure to tobacco smoke - in mums-to-be as "measured by using quantitative immunoassays from maternal serum specimens collected during the first and second trimesters of pregnancy and archived in the national biobank." Indeed, such a biological marker measurement protocol mimics other research from members of this authorship group when looking at maternal nicotine exposure and offspring risk of schizophrenia for example (see here).

Based on the analyses of samples from over a thousand participants born in the late 1990s and diagnosed with ADHD compared with samples from a similar number of non-ADHD control participants, researchers came to their possible *link* observation. They mention how the relationship between maternal cotinine levels and offspring ADHD diagnosis was statistically significant even when other important, potentially confounding, variables were taken into account. When categorising their maternal cotinine results into bands approximating light to heavy nicotine exposure and the possibility of a link with offspring ADHD diagnosis, researchers also reported something that looked like a dose-response relationship. Ergo, a biomarker of nicotine exposure during pregnancy *looked* to be potentially linked to offspring risk of ADHD.

Although important work, my first thought when reading this research was about how these results are 'set' within the context that historically, smoking rates or tobacco exposure rates during pregnancy were so much larger decades ago than they are now (see here), but ADHD is seemingly showing only quite a recent rise in numbers (see here). Although no expert on pregnancy tobacco consumption during the 20th century, I'm assuming that all those adverts about smoking being 'healthy' in the 1940s and beyond (see here) probably meant that quite a few women smoked during their pregnancy in the belief that it was 'healthy'. At the very least, it probably meant that they were exposed to a lot more second-hand tobacco smoke as a result of smoking being allowed in various public places and also more likely to be observed in the home environment. Surely then we would have seen an explosion of ADHD diagnoses at that point in time if the link was so simple? That is, assuming that the tobacco of today is the same as the tobacco of yesteryear.

I'm also intrigued that within the various potentially confounding variables which Sourander and colleagues adjusted for - "maternal socioeconomic status, maternal age, maternal psychopathology, paternal age, paternal psychopathology, and child’s birth weight for gestational age" - there's another variable that could exert an effect on ADHD risk: relative age (see here and see here). Relative age refers to the observation that the youngest children in the school classroom compared to their older classmates, are more likely to be diagnosed with ADHD. It strikes me that alongside something like tobacco or nicotine exposure, so age and other effects could be important.

I'm not trying to poo-poo the link that Sourander and various other research teams have independently observed. I'm also not trying to downplay the harms that tobacco (nicotine) exposure can have for the unborn child. I merely suggest that with typically falling rates of (reported) tobacco exposure during pregnancy in many countries (see here) and increasing levels of childhood (and adulthood) ADHD being reported, there must be other factors at work in any such relationship (see here for example).

The Zheng study represents yet more good scientific value for money as researchers initially sought to "compare the gut microbial communities of patients with SCZ [schizophrenia] and healthy controls (HCs) to evaluate whether microbiotal dysbiosis was linked with schizophrenic episodes or the severity of schizophrenic symptoms." They also "transferred gut microbiota from patients with SCZ into GF [germ free] mice to test whether SCZ-relevant behavioral phenotypes were transmissible via their gut microbiome". The study findings have been covered quite a few media outlets (see here).

The results: "seminal evidence that SCZ is associated with changes in gut microbiota composition that are both specific to SCZ and correlated with symptom severity." This translated into:

the identification of certain bacterial differences between the groups: "the most significant deviations between SCZ and HC subjects occurred for the bacterial families Aerococcaceae, Bifidobacteriaceae, Brucellaceae, Pasteurellaceae, and Rikenellaceae",

a *correlation* between the presence of some bacterial species and the 'severity' of symptoms of schizophrenia,

behavioural changes in those mice who received a gut bacterial transplant from participants with schizophrenia,

"Perturbed gut-brain amino acid and lipid metabolism in SCZ microbiota recipient mice." Gut bacteria produce chemicals (for messaging and the like), and those bacteria transplanted into germ-free mice produced a different cocktail of chemicals that showed up "in the SCZ microbiota compared to the HC microbiota recipient mouse samples." In particular: "lower glutamate and higher glutamine and GABA in the hippocampus."

As I said, the Zheng study was pretty good value for money on the basis of the results obtained. The authors note that their findings "provide a novel framework for understanding the mechanisms of SCZ through the MGB [microbiota-gut-brain] axis and may lead to new diagnostic and treatment strategies."

Caveats? Well, fairly small participant numbers is one thing, as was the potential influence of medication being taken by those with schizophrenia. Authors however mention that: "we found that the distributions of global microbial phenotypes did not vary between medicated and unmedicated patients with SCZ." I'll also point out the inherent 'difficulties' when talking about "SCZ-relevant behaviors in GF recipient mice" similar to that noted with regards to other diagnostic labels (see here). People are given labels like schizophrenia not mice.

But it's a good start and complements other work in 'related' areas talking about the gut-brain axis as being potentially pertinent to 'some' schizophrenia (see here and see here). Whether modifying gut bacteria via use of something like diet, probiotics or the horror that is the gut microbial transplant might relieve some of the signs and symptoms of schizophrenia is an area that requires quite a bit more investigation...

Familiar because HRQOL was found to be "substantially lower in an ambulatory population of adolescents and young adults with ME/CFS than for healthy controls in North America" in the Roma study, in keeping with other studies looking at this important parameter (see here). Familiar also because PEM - post-exertional malaise - was found to be something really quite important to ME / CFS, again in line with other findings (see here for example). But don't think that the Roma findings aren't important, they are. Indeed, with mention of something called orthostatic intolerance in the context of CFS / ME, they provide some further directions for investigation.

So: "We enrolled 55 consecutive ME/CFS patients (46 F) aged 10–23 years." They all "satisfied the 1994 International Chronic Fatigue Syndrome Study Group criteria" (also called the Fukuda criteria). Importantly too: "Individuals with primary depression who were referred by psychiatrists for evaluation of chronic fatigue were excluded, but those who had developed depression sometime after the onset of ME/CFS were included." See those words 'developed depression... after the onset of ME/CFS'. Control participants (n=55) - asymptomatic and in good health - were also included for study. Quite a large battery of questionnaires and schedules were delivered to participants covering HRQOL and quite a bit more including fatigue and depression. Researchers also asked a few questions about "the type of onset for ME/CFS" as well as items pertinent to the IOM (United States Institute of Medicine) criteria for ME/CFS. Lots to see.

And indeed, the results were pretty revealing. Yes, HRQOL was lower - significantly lower - in the ME/CFS group, as talk about a percentage of those with ME/CFS having to change from regular schooling "to part-time schooling... [or] home tutoring" tells you everything you need to know (yet again). Also: "A novel finding of this study is the correlation of impairment in HRQOL with the frequency of PEM, at least for an ambulatory population with ME/CFS." PEM, or 'payback' as another study categorised it as (see here), is starting to get the clinical and research attention that it truly deserves. Researchers specifically mention how "as the frequency of PEM increased, the mean PedsQL [Pediatric Quality of Life Inventory] score fell and the mean FDI [Functional Disability Inventory] score increased, consistent with a significant association of PEM with worse overall function." Need I say anymore?

And then back to orthostatic intolerance (i.e. the "development of symptoms when standing upright which are relieved when reclining"). Researchers considered this present in participants if "(a) self-reported lightheadedness occurred at least several times per week, (b) there was a history of recurrent syncope in the presence of a structurally normal heart, considered consistent with NMH [neurally mediated hypotension]... or (c) previous upright tilt testing or a passive standing testing (performed in patients not being treated with medications for orthostatic intolerance) had confirmed the presence of NMH or POTS [postural tachycardia syndrome]." And present it was in 96% of participants. So much so that authors decided that with orthostatic intolerance being one of the core diagnostic criteria for the IOM diagnostic criteria for ME/CFS, 85% of their participants hit the diagnostic thresholds based on that scheme. Important stuff.

This takes us neatly back to the quote titling this post: "PEM, cognitive impairment, and orthostatic intolerance as core symptoms of pediatric ME/CFS." And perhaps a change is coming to research and clinical practice in this area. Having said that, change is going to be quite difficult for some groups it seems [2] as words like: "Parental representations could contribute to fatigue maintenance" still appear in the peer-reviewed science literature with CFS/ME in mind...

[2] Loades ME. et al. Perfectionism and beliefs about emotions in adolescents with chronic fatigue syndrome and their parents: a preliminary investigation in a case control study nested within a cohort. Psychol Health. 2019 Mar 1:1-17.

Monday, 25 March 2019

'Favourable outcomes' is a term mentioned in amongst the various findings reported by Robin Goin-Kochel and colleagues [1] following their examination of "dose compliance, attrition, and potential side effects of short-term, high-dose carnitine supplementation" in a small group of boys diagnosed with an autism spectrum disorder (ASD). Understanding that the Goin-Kochel study was primarily directed at looking at safety, on the basis of 'high-dose' carnitine supplementation, it appears that an elevation of plasma carnitine and related metabolites was not the only effect noted in their small cohort (N=10).

Tracking back slightly, carnitine is an important compound. Not quite an amino acid, carnitine plays an important role in energy production; as per use of the word 'mitochondria' and it's transporting duties of long-chain fatty acids to the cell powerhouse for energy conversion. You probably won't be surprised to hear that carnitine has a *connection* to some autism (see here and see here). Indeed, Goin-Kochel et al mention the findings reported by Patrician Celestino-Soper and colleagues [2] and their identification of a genetic issue that impacts on 'carnitine biosynthesis' in some people diagnosed with ASD. At least one of the authors on the Goin-Kochel paper has some pretty important knowledge about that finding of trimethyllysine hydroxylase epsilon (TMLHE) gene issues in the context of autism...

Alongside looking for reports of any side-effects from the use of carnitine - "oral suspension or tablets of levocarnitine in 3 divided doses, starting at 200 mg/kg/day and increasing to 400 mg/kg/day, with a maximum daily dose of 6 g" - various behavioural schedules were included in the study protocol. Some were objective measures of autism symptomatology; others were parent-report measures. The use of the Clinical Global Impression Scale (CGIS) also provided a helpful 'clinicians' overview' of before and after supplementation in this open-trial.

Results: a few side-effects coinciding with carnitine use were reported. These included: "heavy odor (4 parents), diarrhea (4 parents), and sporadic vomiting (1 parent)." Such reported side-effects meant that three children remained at the lower dose of carnitine over the experimental period (8 weeks).

Alongside, a few other 'favourable outcomes' were also reported: "calmer behavior (2 parents), more energy (2 parents), increased prosocial behaviors (4 parents), greater awareness (2 parents), better eye contact (2 parents), and improved language skills (2 parents)." These parental reports were accompanied by some 'changes' noted on the various schedules included in the study protocol, including those CGIS ratings. The authors used the study results produced by Geier and colleagues [3] as their comparator; highlighting how both studies had picked up "improvements in overall ASD symptoms... and some language ratings." Importantly too, Goin-Kochel et al talk about how none of their cohort were rated as "worse at post treatment."

Where next? More research please. Bigger participant numbers, more methodologically sound study designs and perhaps also, investigation of the potential pros-and-cons of carnitine supplementation over a longer period of time. By all means keep an eye on those side-effects and perhaps look to the biochemistry as to why such side-effects might appear; indeed look to the biochemistry for potential best-responders to this type of intervention too ("One child had documented TMLHE deficiency and 3 had low carnitine levels" in the Goin-Kochel cohort). But more study is definitely indicated...

The question at hand: how should one conceptualise autism? Is it truly a spectrum as per the Lorna Wing proposition, or is it something a trifle more complicated? As per the title of this post, should we perhaps be thinking about autism as some sort of "multi-dimensional cluster of spectrums?" I'll come back to that idea shortly.

Well, it's not for me to make definitive conclusions on this blog. Science rarely, if at all, provides an absolute 'truth' but rather the probability that something is approaching truth. Such a notion goes double when you consider the singular label of autism and the huge heterogeneity that it encompasses. There are no easy answers and probably little or no truths.

Starting with the Kim paper (including some notable names such as the surname 'Gadow') and the name of the research game was modelling, modelling in a computational sense. So: "The sample comprised 3,825 youth, who were consecutive referrals to a university developmental disabilities or child psychiatric outpatient clinic." The CASI-4R - formulated by Prof. Gadow - was the schedule administered, which includes "an ASD [autism spectrum disorder] symptom rating scale" among other things. Some nifty statistics were applied to the data and the initial findings were 'tested' on a further group of over 2500 children.

Results: "Based on comparison of 44 different models, results indicated that the ASD symptom phenotype is best conceptualized as multi-dimensional versus a categorical or categorical-dimensional hybrid construct." And the dimensions mentioned in that 'multi-dimensional' statement? Well, lucky for us they were something familiar: "social interaction, communication, and repetitive behaving."

Then to the Duffy/Als paper (again, these authors are no stranger to autism research) and a similar starting point: "The authors postulate that the broad definition of an omnibus 'spectrum disorder' may inhibit delineation of meaningful clinical correlations." Indeed, very familiar (see here). The conclusion: "evidence that an objectively defined, EEG [electroencephalogram] based brain measure may be helpful in illuminating the autism spectrum versus subgroups (clusters) question." The tool used by Duffy/Als in their study was something called NbClust "specifically designed to provide an objective means, i.e. independent of investigator choice, to identify the ‘optimal’ cluster number within a population." Said tool was applied to EEG data derived from 400 participants diagnosed with an ASD. Statistics and more statistics applied to the data revealed that: "430 subjects diagnosed as being on the autism “spectrum” and represented by 40 EEG coherence factors..., fell into two distinct clusters." These autism spectrum clusters differed from each other and importantly, from "554 subject neuro-typical control group subjects, not involved in the clustering process." Interesting results but an unfortunate use of the term 'neurotypical' (see here). Duffy & Als conclude that their data support a view whereby "autism disorder should not be seen as a continuous spectrum." So Kim & Duffy/Als arrive at similar conclusions: a singular 'spectrum' idea of autism is probably not the best way of conceptualising the essence of the label.

I would perhaps add in a little more evidence for the idea that 'multi-dimensional clusters of spectrums' is a potentially better fit. I used the words 'spectrums' (plural) because there is a growing body of evidence to support the idea of more than one 'type' of autism. I say that from the perspective of evidence for autism being 'acquired' under several different circumstances (e.g.accompanying inborn errors of metabolism, linked to exposure to certain infections or diseases, etc). There's also evidence that clinical profiles under the umbrella term autism are not uniform (e.g. regressive autism, the so-called 'optimal outcomers', differing developmental trajectories, etc). And when one looks at something like the success (or not) of intervention, it's plain to see that there is no universally shared genetics and/or biology of autism in the singular either (see here and see here for examples). Add in the idea that autism rarely appears in a diagnostic vacuum (see here) and that said comorbidity might 'cluster' in some subgroups of autism (see here), and I hope you can see why 'plural' might be a good addition to any attempt to re-conceptualise autism: spectrum, dimension, tapestry, cluster or however you think it should be defined...

Oh, and since we're on the topic of trying to conceptualise autism, a new book out recently has been reviewed in Nature (see here). It talks about how "conclusive findings about sex-linked brain differences have failed to materialize" which is particularly apt in relation to previous talk about 'extreme male brains' as a way of conceptualising [some] autism (see here). One quote I particularly liked from the review is this one: "The brain is no more gendered than the liver or kidneys or heart."

Friday, 22 March 2019

The quote heading this post - "To examine associations between early developmental exposure to ambient pesticides and autism spectrum disorder" - reflects the aim of the study published by Ondine von Ehrenstein and colleagues [1]. Said aim was accomplished by examining data from "California’s main agricultural region, Central Valley, using 1998-2010 birth data from the Office of Vital Statistics" with regards to autism diagnoses (see here) and pesticide use and exposure. The results: "Findings suggest that an offspring’s risk of autism spectrum disorder increases following prenatal exposure to ambient pesticides within 2000 m of their mother’s residence during pregnancy, compared with offspring of women from the same agricultural region without such exposure." Also: "Infant exposure could further increase risks for autism spectrum disorder with comorbid intellectual disability."

I don't want to linger too much on the von Ehrenstein study but a few points are worth noting. The question of what specific pesticides *might* influence risk of offspring autism is a complicated one. The researchers reported that "small to moderately increased risks for the disorder in offspring with prenatal exposure to the organophosphates chlorpyrifos, diazinon, and malathion, the pyrethroids permethrin and bifenthrin, as well as to glyphosate, avermectin, and methyl bromide" were observed. They (and the editorial) talk about how further research is required to "examine the joint effects of multi-exposure mixtures to more effectively protect human health." This is important in the context of other research (see here and see here) and also to avoid any big media headlines (see here) about specific preparations 'causing' autism (which has not yet been authoritatively established). Given that various different classes of pesticides have somewhat slightly different biological actions, there is a lot of work to be done on the possible biological mechanisms/targets and any synergistic effects.

Also: "children with autism spectrum disorder and co-occurring intellectual disability were examined as a separate outcome." The fact that von Ehrenstein et al observed something like a 'stronger association' between pesticide exposure and those at the "more severe end of the autism spectrum" (the description according to one media source) is another important point requiring further study. I say this in the context that 'comorbidity' might not always be the best description for symptoms and diagnoses accompanying autism (see here).

The authors conclude that their findings - with appropriate caveats - have implications. Namely: "Exposure of pregnant women and infants to ambient pesticides with a potential neurodevelopmental toxicity mode of action should be avoided as a preventive measure against autism spectrum disorder." I don't think too many people would disagree with the sentiments of 'avoiding pesticide exposure' particularly for pregnant women and those who might also be more vulnerable to their potential effects. The questions now turn to genetics and biology and the question of why...

For those who might not know the background to this story, the article written by John Donvan & Caren Zucker [3] back in 2016 provides an excellent overview. It charts how the man who defined the (now defunct) label of Asperger syndrome worked in some pretty dark times. The depiction of Asperger during the years of Nazi occupation for many years was one of "a cautious yet brave and canny saboteur of the Nazi project to exterminate intellectually disabled children." Donvan & Zucker note that "an overwhelmingly positive narrative of Asperger as a man of moral rectitude came into focus in the new millennium, elevating him almost to the status of hero."

But as far back as the 1990s, not everyone was convinced by this narrative. Indeed, as Asperger syndrome made it's [fairly brief] entry into one version of the DSM, one of the diagnostic 'bibles' used to diagnose autism and a whole host of other behavioural and/or psychiatric conditions, questions were already being asked and not just by one person. It took however another 20 years or so before a historian, Herwig Czech, did some real 'digging' and presented the results of his research. Czech's conclusions were summarised by Donvan & Zucker: "Asperger took care during the war to safeguard his career and to burnish “his Nazi credibility.” Asperger, it would appear, did what was necessary."

The Falk paper talks about 'newly translated' information but really doesn't provide much more data than that which was already unearthed by Czech and other researchers/writers. We're told that various on-line translation services were used to translate several documents; specifically looking at "cultural contexts, Asperger's sustained campaign on behalf of disabled children, and his attitude toward patients."

I've read the full-text of the Falk paper and have to say that I really can't see how it substantially changes some key points. One primary issue is that Asperger seemed to have referred a child - Herta Schreiber - "from the University of Vienna Children’s Clinic to Am Spiegelgrund, where they [children] were murdered between 1940 and 1945." Spiegelgrund was a facility "which superficially resembled a hospital, but which functioned in reality as a killing center for severely disabled children." One might quibble about some of the translations and what was meant by them in terms of intent, but for Herta, such a referral apparently signed by Asperger, was her death sentence: "On 2 September, a day after her third birthday, Herta died of pneumonia, the most common cause of death at Spiegelgrund, which was routinely induced by the administration of barbiturates over a longer period of time." Did Asperger know about what really went on at Spiegelgrund? Certainly other doctors who Asperger worked with seemed to know what was going on there including some of his colleagues and direct superiors. Surely also, given the very consistent number of deaths from 'pneumonia' - many only a matter of weeks after children were referred to Spiegelgrund - most doctors would be questioning what was going on there if they didn't already know. And then we have the post-war picture, and how little was seemingly said about children like Herta by Asperger after the true nature of facilities like Spiegelgrund came to light...

We can never truly know what went on during those dark years. We rely on incomplete records that have been meticulously pieced together to provide a picture; albeit an incomplete picture. Asperger died in 1980 so he is not around to answer the points raised and defend himself. But never forget that Herta was a child. She was 3 years old when she was murdered. On the basis of that important fact alone, and the apparent referral made by Asperger to the place of her death, I find the Falk paper mentioning the word 'non-complicit' to be distasteful and disrespectful to her memory. I similarly find the campaign to restore the 'hero status' of Asperger distasteful and disrespectful to her memory and many others who were considered less than human by such a disgusting regime. To quote from the Donvan & Zucker piece once more: "Czech spoke for only 20 minutes or so that day at the Vienna City Hall. Then he stopped to take audience questions. In that pause, Dr. Arnold Pollak, the director of the clinic where Asperger had worked for much of his career, leapt to his feet, clearly agitated. Turning to the room, he asked that everyone present stand and observe a moment of silence in tribute to the many children whose long-forgotten murders Herwig Czech had returned to memory. The entire audience rose and joined in wordless tribute."

Wednesday, 20 March 2019

The findings reported by Daniela Čiháková and colleagues [1] provide the rather long blogging fodder today, and some interesting observations on how the immune system 'reacting' to gluten in some cases of schizophrenia might have some pretty far-reaching consequences when it comes to other proteins with a similar chemical structure.

OK, first things first, gluten is a protein. It's made up of long chains of amino acids; the building blocks of proteins. As gluten is digested in the gastrointestinal (GI) tract, various enzymes get to work on the protein to break it down into it's constituent amino acids, forming peptides (short chains of amino acids) along the way. The protein gluten and its components like gliadin has a characteristic shape like every protein has. For reasons that aren't yet completely understood, the immune system of some people can sometimes 'mark' normally fairly harmless proteins like gliadin as something that needs dealing with. It does this via the production of antibodies. Antibodies usually mark pathogens like bacteria or viruses, and by doing so, set off a cascade of biological processes to [try and] ensure that such invaders don't take hold and also to remind the immune system of what to look out for. Marking something like gliadin out (which is neither bacteria nor virus!) probably means that the body is detecting gliadin in places it shouldn't be; something that I'll come back to in a minute.

It's not beyond the realms of possibility that when the immune system marks a specific protein as something to keep an eye on, it can make mistakes. If for example, two proteins 'look' similar to each other in a chemical arrangement sense, despite being different proteins with different functions, the immune system can sometimes become a little confused and start to mark both as being an invader on the basis of one already having 'special interest' status. Several descriptions describe such a process: "cross reactivity or mimicry." This accidental marking can sometimes have important repercussions, where such a process is thought to be a basis for autoimmunity.

Čiháková et al detail findings suggesting that just such a process - mimicry - could well be pertinent to some cases of schizophrenia. As already mentioned, they started with the observation that some people diagnosed with schizophrenia have high levels of specific antibodies to gliadin (see here and see here). This follows quite a lot of history linking gluten and schizophrenia together (see here). They wanted to see if as well as presenting with antibodies to gliadin, a cohort of people diagnosed with schizophrenia might also present with elevated antibodies to something called GRINA - Glutamate Ionotropic Receptor NMDA type Subunit Associated with protein 1. They focused in on GRINA because it has a "similar protein structure to gliadin representing a potential target for cross reactivity or mimicry." GRINA also links into glutamate system functioning, something which has also already been mentioned with schizophrenia in mind (see here).

There's another detail about the Čiháková study which relates to a point I touched upon earlier, on the possible hows-and-whys of gliadin antibodies being found in cases of schizophrenia: enhanced gut permeability a.k.a leaky gut. Researchers also analysed serum samples for the presence of something called Anti-Saccharomyces Cerevisiae antibodies (ASCA) which they say are "related to gut permeability." This follows other research in a similar vein (see here) and the suggestion that something like abnormal gut permeability *could* be implicated in some cases of schizophrenia.

Results: looking at serum samples of 160 people diagnosed with schizophrenia and 80 not-schizophrenia controls, researchers observed "a higher prevalence of positivity to ASCA IgA... and IgG" in those with schizophrenia. This tallies with the leaky gut hypothesis. They also reported that "GRINA IgG was higher in schizophrenia patients than in healthy controls." Putting these results together, they concluded that the mimicry hypothesis might well be pertinent to some schizophrenia.

There is a lot more work required in this area for sure. This will need to involve further investigation of the hows-and-whys of any such mimicry, and whether such a process could be a potential target for intervention. Indeed, in that intervention vein, I'm wondering whether use of a gluten-free diet for some with schizophrenia who have such antibodies (to gluten and other things like GRINA) might be an option. There's also merit in looking further at the issue of gut permeability and schizophrenia; whether again adoption of a gluten-free diet (which can positively affect gut permeability measurements) might be indicated, perhaps alongside other therapeutic targets.

But this area of research is interesting, and adds to the quite long research history linking food components and some behavioural / psychiatric labels...

Tuesday, 19 March 2019

A recent (online) newspaper report from here in Blighty included the quote used in the title of this post: "his sudden interest in changing gender may have been another of his autistic obsessions" (see here).

The report describes how a male - born biologically male - teenager diagnosed with autism expressed an opinion that "he believed he was female" and how his opinion was received by his parents and other professionals. Differences in the reception and perception of that opinion eventually led to some 'frustration' and, worryingly, the eventual intervention of social (child) services.

I decided to blog about this report primarily because (a) it ties in with some important peer-reviewed science discussions about gender identity and autism (see here and see here), and (b) there is a distinct possibility that the headline accompanying the report - "Social services threaten to take autistic boy into care after his parents refuse to let doctors give him powerful sex-change drugs" - is likely to be replicated again. Such a headline also taps into some wider debates about an increasing number of children talking about their gender and the decision-making rights and abilities of children both on and off the autism spectrum.

First things first, I know there are lots of strong opinions about sex and gender and 'what's right for children' these days. I don't offer an opinion either way nor do I claim to be an expert on issues such as gender dysphoria - "where a person experiences discomfort or distress because there's a mismatch between their biological sex and gender identity" - or gender reassignment or related issues. As mentioned, I'm interested in the science behind such discussions because autism has been discussed, on more than one occasion, as being potentially 'over-represented' among those with gender dysphoria [1] and/or wanting to/going through gender reassignment services. I say 'potentially over-represented' but wouldn't want anyone to think that any scientific debates have been settled at the current time: they haven't [2] (see here). I'm also interested in this topic because, aside from any gender reassignment issues, autism not so long ago was faced with something called the 'Lupron protocol'. Then leuprorelin, a drug sometimes used to 'delay puberty', was touted as something important to autism for very, very different reasons. I might add that the story of such a 'protocol' did not end well, as words like 'chemical castration' were banded around (see here).

I selected the quote that heads this post because it strikes me that there are some 'unique' issues that arise in the context of autism being mentioned alongside gender dysphoria and/or reassignment. Issues that don't seem to have been properly considered at the time of writing. Indeed, when I first tweeted about the source article for this post, a couple of response summed up the positions taken. First: "That child is not a boy. She is a girl and she needs the medical transition that will treat her dysphoria and allow her to live her best life." Another response was from someone who is themselves autistic and mentioned an important word: 'impulsivity'. Indeed, the article itself also mentions some similarly important phrases which require consideration. So: "they [his parents] suspected his abrupt decision to change sex was a result of his autism" and "All we were doing was trying to get him to pause and think about his actions" and "The school and social workers took what our child said as gospel. But considering he has autism, his perception of social scenarios is seen through an autism lens." An autism lens?

As you can see, a lot of those quotes/opinions focus on the idea that the traits that stem from or follow autism are potentially important to this debate. Minus any 'pity me' sentiments, they imply for example, that autism confers some specific 'vulnerability' that cannot simply be brushed under the carpet particularly when a person makes, or wants to make, important, potentially life-changing, decisions. I've talked about the issue of vulnerability and autism before on this blog (see here and see here) with some equally life-changing issues in mind. The topics differ but the sentiments remain the same. It's highly likely that the parents discussed in that news report know a little a bit about such vulnerability and autism purely in the context of raising their offspring.

Such vulnerability does however have to be balanced with individual rights; that is the rights of an individual to make important decisions that affect them. Such decisions might not always be 'the correct ones' or the ones that significant others necessarily want them to make but nonetheless, still need to be valued particularly within the context of assumed competence (see here). Indeed I get the impression that it's the possibility that the child has expressed an opinion with future consequences - "My biggest worry as a mum is my child gets pushed down this route, becomes a woman, goes through the surgery, then gets to 25 and says, “I’ve made a mistake.”" - that seems to worry the parents in the news report more than anything else. The use of the word 'surgery', implying the degree of 'invasiveness' needed and potentially also inferring 'irreversibility', is perhaps also an important part of their response.

Ultimately there are no easy answers to the issue described in today's post despite some significant strength of feeling. What will help however, is research; good quality research that is not afraid to test difficult hypotheses. And whilst individuals should always be empowered to make decisions for themselves, there should always be an appreciation that decision-making typically does not occur in a vacuum...

Monday, 18 March 2019

It took a few attempts for me to get this blog post discussing the the paper by Carlo Alessandria and colleagues [1] right. The reasons? Well, predominantly it was because I'm no expert when it comes to the gastrointestinal (GI) tract and autism and, in particular, some of the intricacies of the clinical findings in that context. Don't get me wrong, I am a very keen observer of the peer-reviewed science literature on the bowel and autism (see here and see here and see here for examples) but I'm no gastroenterologist.

What I did take away from the Alessandria findings is that science is continually looking at the possibility of a link between the various GI issues identified in cases of autism and the still-important peer-reviewed literature on how use of a gluten- and/or casein-free diet (GCFD) seems to have a positive impact for some people on the autism spectrum (see here). Indeed, that there may be lots more to see when it comes to a gut-diet-behaviour interface in relation to (some) autism...

So, slowly does it. First, the aim of the Alessandria study: "evaluating the distribution of human leukocyte antigen (HLA)-DQ2/DQ8 typing among patients with ASD [autism spectrum disorder] with GI symptoms, together with its correlation with duodenal histology and response to GCFD."

HLA-DQ2/DQ8 'typing' are words more commonly found in relation to the prototypical 'dietary gluten can affect health' condition that is coeliac disease. They describe some of the genetics of coeliac disease (CD), and are key components involved in risk for the condition and perhaps other diagnoses of a similar autoimmune ilk. From the 150 or so participants - "with ASDwith GI symptoms referred to our outpatient clinic" - who were screened for HLA-DQ2/DQ8, around half were positive (72/151). But researchers did not just stop there. Alongside they also screened for "CD-specific antibodies" (see here and see here for the flavour of what this includes) and concluded that "134 (89%) were negative." To summarise, around half of participants with autism and bowel symptoms possessed the genetics of coeliac disease. But, only around 10% showed a pattern of antibodies related to CD indicative of an immune response to gluten as well as other issues (see here).

And there was more: "Patients were prescribed a 6-month GCFD, and then clinically reassessed." This is where another 'assessment' also becomes relevant to the Alessandria findings. As part of their clinically indicated procedures, participants also underwent endoscopy. This allowed researchers to both look at the inner workings of some of the GI tract and also potentially take biopsy samples. At baseline, before any diet was put in place, they observed that: "56 (37%) showed duodenal microscopic inflammation." 'Duodenal' refers to the duodenum, a part of the GI tract fairly close to the exit of the stomach. Inflammation means just that. And something interesting seemed to connect such bowel findings and dietary response: "Response to diet was related to the presence of histological duodenal alterations at baseline (odds ratio 11.323, 95% confidence interval 1.386-92.549 for Marsh 2 pattern)." In other words, and accepting that correlation is not the same as causation, issues identified in the duodenum - "duodenal histology" - seem to be a possible predictor of response to a gluten- and casein-free diet in relation autistic people.

There is a need for lots more study in this area. Alessandria and colleagues reported their observations on the basis of patients presenting at their clinic with medical needs. This was not a clinical trial in the respect of being randomised (e.g. receiving a diet or not or some other medication to treat such identified bowel issues) or being blinded (researchers and patients not knowing who got what intervention). Knowing a little bit about the use of a GCFD in the context of autism (see here) I'm also acutely aware that 6 months following such a diet is a long time. Even with the best will in the world, some people will not be able to follow such a restrictive diet day-in, day-out. There are issues.

But the Alessandria results are important and promising. They provide a template for further study and an addition to the wealth of biologically-based information on who, on the autism spectrum, might be a 'best candidate' for dietary intervention which excludes gluten and/or casein. I know some people might start up with the 'it's too invasive' arguments in relation to the use of endoscopic and indeed, colonoscopic inquiry when it comes to autism. My counter-argument is that if physicians were presented with a child or adult who did not have autism yet had the same bowel problems as this and other cohorts, would they not be afforded the best healthcare available to them including such inquiry? And why then should a diagnosis of autism but exclusionary to accessing such healthcare? Oh, and it's worth mentioning that at least one of the authors on the Alessandria paper has talked about how technology might eventually make such invasive techniques that little less invasive [2]. Indeed, they've also talked about what else aside from a gluten- and casein-free diet might be clinically indicated for some people on the autism spectrum [3] too with GI issues in mind...

[2] Balzola F. et al. Panenteric IBD-like disease in a patient with regressive autism shown for the first time by the wireless capsule enteroscopy: another piece in the jigsaw of this gut-brain syndrome? Am J Gastroenterol. 2005 Apr;100(4):979-81.

The Sharpe paper concerns the PACE trial, the study which reported that "when added to specialist medical care, cognitive behaviour therapy and graded exercise therapy were more effective in improving both fatigue and physical function in participants with CFS [chronic fatigue syndrome], than both adaptive pacing therapy and specialised medical care alone."

Anyone with a little bit of knowledge about the PACE trial will know that it's a 'contentious' topic within CFS (and ME, myalgic encephalomyelitis) circles. Indeed, the Sharpe paper comes about as a direct result of a reanalysis paper (see here) which reported findings raising "serious concerns about the robustness of the claims made about the efficacy of CBT [cognitive behavioural therapy] and GET [graded exercise therapy]" in the context of CFS/ME. 'Serious concerns' is putting it mildly considering how others have described the PACE trial and some of its tenets (see here).

Sharpe et al, who were authors listed on the original PACE trial paper [2], have had to defend their work/findings before in the peer-reviewed realm (see here). Same as before, the name Carolyn Wilshire is addressed and her teams reanalysis of the PACE trial data [3]. Said data was, I might add, (partially) released only following intervention from the Information Commissioners Office (ICO) here in Blighty (see here). More recent events have similarly reiterated that 'access to raw study data' is something that CFS/ME researchers perhaps need to bear in mind at study conception (see here).

I'm not going to clinically dissect the Sharpe paper in this post because (a) 'interpretation' forms quite a bit of the reply to the Wilshire reanalysis, and (b) your opinion on the scientific quality of the Sharpe reply is most likely going to be shaped by where you stand in terms of the whole CBT/GET for CFS/ME discussion. Indeed, a peer-reviewer of the Sharpe paper also said as much (see here). What I will comment on is how the Wilshire reanalysis paper and the more recent Sharpe reply to the reanalysis paper might further inform research more generally with CFS/ME in mind.

Point 1: Design a good trial analysis plan and stick to it. From my 'outsider looking in' perspective, the changes made to "the scoring of the pre-specified outcomes" regarding fatigue and physical functioning in the PACE trial, however innocent they might have been, have created tension. Lots of tension. Such changes, whether agreed by "Trial Data Monitoring and Steering Committees" or not, can be construed in various different ways. It's better not to make such changes in the first place.

Point 2: If you are going to study something like physical functioning in relation to CFS/ME, don't just rely on things like questionnaires and Likert scales; use actigraphy too. Self-report is always a good thing but I've never understood why, with the wide range of cost-effective technology out there (available I believe, even in the early 2000s), wearable trackers such as pedometers or similar were not also utilised during such studies (see here). If you're spending £5 million on a trial, a few quid for some pedometers is not exactly going to break the bank and will inevitably bring some further quality data to the table.

Point 3: Recovery. As per other discussions (see here), most people would characterise recovery as a complete remission of symptoms and/or return to typical functioning. If you're not going to use this description, don't use the word recovery. Use something else instead. Indeed, use 'partial remission' or 'improvement' if you need to but don't call anything less than the complete remission of symptoms 'recovery'.

Point 4: Long-term outcomes. It's probably best to avoid any sweeping statements after the arms of a trial - a "randomised trial" not necessarily a "randomised controlled trial" according to Wilshire et al - have been completed. More so when you're measuring such long-term outcomes via a postal question minus any objective measure(s) (see point 2). It's probably also a good idea to ask patients about their quality of life too and whether that has changed (see here).

Point 5: Even if your paper states in no uncertain terms that: "The effectiveness of behavioural treatments does not imply that the condition is psychological in nature" the use of something like CBT for CFS/ME implies that you probably think there is a substantial psychological 'component' to the condition. This is compounded when you're for example, a Professor of Psychological Medicine. If you were pitting CBT in particular against a specific pharmacological or biological intervention 'for CFS/ME' (see here for example), I'd be more inclined to see your view in a more 'rounded sense'. Indeed, if you were to study one or two biological parameters as well as behavioural ones looking for any change following intervention, you might convince more people that psychology is not the primary line you take. And whilst on the topic of psychology and CFS/ME, it's probably also best not to use 'psychobabble' terms like 'deconditioning' in your research. Such terms are pretty much scientifically untestable and, given the recent discussions about the legacy of some adherents to something like psychosomatic research (see here), is likely to be consigned to the scientific dustbin as some later point.

I think I've covered the main points as I see them. Please feel free to agree/disagree as you wish.

I mentioned two words in the title of this post - prevalence and incidence - which perhaps need further explanation. Prevalence refers to the number of existing cases of a condition / disorder / disease, typically expressed as a proportion of a population. Incidence is more about the number of new cases of a condition / disorder / disease during a specific period of time. Hamad et al reported data on both measures, where "1685 ASD cases were diagnosed between 2004 and 2015."

So: "The crude ASD prevalence increased from 0.46% in 2004 to 0.97% in 2015" and "The crude incidence rate increased from 0.16% in 2004 to 0.39% in 2015." These combined findings illustrate that the number of cases of diagnosed autism in young children in Manitoba over the period of 2004 and 2015 was not static; more and more people were being diagnosed, and with an increasing rate of diagnosis.

What's more to say? Well this data puts another nail in the coffin to the old 'autism isn't increasing' argument that has slowly fizzled out over the past decade or so. Autism diagnoses are on the increase; and as per the Hamad focus - preschoolers and toddlers - at least some of the increase is in the young and not just older children and adults who might have 'slipped through the diagnostic net'. Next questions: why and what? Why is autism still on the increase? What factors are driving the increase? And please, enough with the 'increasing awareness' dogma on this question...

Thursday, 14 March 2019

The quote heading this post - "Our findings beg the question, what is going on with these children who no longer have an ASD [autism spectrum disorder] diagnosis?" - comes from some media coverage of the findings reported by Lisa Shulman and colleagues [1]. Shulman et al (bravely) set about examining an important phenomenon in autism research and practice circles: those who were previously diagnosed as being autistic / having autism but at a later date 'no longer met the diagnostic criteria for autism'.

I've talked about these so-called 'optimal outcomers' quite a bit on this blog (see here and see here and see here for examples). I know such discussions aren't everyone's cup of tea, particularly those who see autism as so much more than a diagnostic label, perhaps akin to an identity. The fact of the matter is however that there is what I would call 'substantial evidence' in the peer-reviewed science domain and beyond that the idea that 'autism is a lifelong condition/disorder' does not necessarily cover the huge heterogeneity encompassed under the label autism. Some people, for whatever reasons, do not reach critical diagnostic cut-off points for autism on a lifelong basis.

So, what did Shulman and colleagues do and find? They reviewed the clinical records of over 500 children who were diagnosed with autism or autism spectrum disorder (ASD) at a specific clinic. Most were aged around 3 years old when first diagnosed and were followed up about 3-4 years later. Importantly most of the children participated in one or more intervention programs aimed at improving skills and the like and (hopefully) quality of life. Again, although not everyone's cup of tea, the words 'applied behavioural analysis' (ABA) are also mentioned as an intervention; something that has been discussed in the context of optimal outcome before (see here).

Shulman et al noted that 38 children, equating to around 7% of their group (38/569), "subsequently experienced resolution of ASD symptomatology and no longer met diagnostic criteria for ASD at follow-up." This figure (7%) is not a million miles away from other figures noted in other independent studies (see here and see here).

Further examination of records however revealed that not meeting diagnostic cut-off points for autism did not necessarily mean 'symptom-free' as various other symptoms/conditions were noted in about two-thirds of their 'optimal outcomers'. This included language disorders, attention-deficit hyperactivity disorder (ADHD) and even the signs and symptoms of psychosis in a few. Three of the 38 optimal outcome children were noted to be completely symptom-free (described as 'recovered from autism' with no other issues); something that has again been noted in other studies too (see here).

Then back to that quote titling this post: what is going on with these children who no longer have an ASD diagnosis? I'm sure some people will put it wholly down to initial misdiagnosis. Y'know, something along the lines of 'they weren't autistic in the first place' despite the fact that they previously met clinical cut-off points for a diagnosis. Minus sweeping generalisations, misdiagnosing autism is not something that can be completely taken off the table as per other examples in the peer-reviewed literature and beyond (see here and see here). Indeed, if one ventures down the pathway of misdiagnosis as accounting for results such as those by Shulman and colleagues, one must logically then assume that such misdiagnosis is pretty widespread (at least in 7-12% of cases of autism). Such a situation also plays into other ideas too; particularly how self-diagnosis of autism is even more dangerous than has been hitherto suggested (see here and see here) with regards to the risk of misdiagnosis.

Other people might talk about things like 'masking' as accounting for such optimal outcome, where symptoms are merely being consciously hidden by those with autism (see here). It's an important area of study by all means but seriously ask yourself the question: how likely is it that a 6 or 7-year old child would be able to mask some fundamental signs and symptoms of autism so as to mislead a professional clinician that they didn't have autism having previously met cut-off points? Adults, yes perhaps some (see here). But young children? Be honest now...

Personally, I'm inclined to believe that at least some of those optimal outcome cases are genuine. That is, children (and adults) did meet the diagnostic criteria and clinical cut-off points for autism (including the criteria about symptoms significantly affecting day-to-day life) and then for whatever reason(s) symptoms abated. Intervention certainly could have played a role, but I'm also inclined to believe that behavioural intervention in particular, does not have the power to render someone who was autistic to be not-autistic. I know some big claims have been made about certain interventions down the years, but I've seen little [longitudinal] convincing evidence in the peer-reviewed literature yet.

There must be other factors at work. There must, for example, be a biological element to this. And as one example, just head back to all those discussions about certain types of infection potentially *leading* to the presentation of autism or autistic traits (see here and see here) as a possible template, and the outcomes mentioned for some. One possibility at least.

Much like discussions on another sometimes contentious topic - regression and autism (see here and see here) - there's enough peer-reviewed science literature to suggest that optimal outcome (or however you want to describe such 'growing out of' issues) is a very real scenario for some. Not all, but for some. And so once again the call goes out to start studying the genetics and biology of these so-called optimal outcomers, and then ascertaining whether any findings might have some important implications more widely for the [plural] label of autism...

ABOUT AUTISM SPECTRUM CONDITIONS

Autism or autism spectrum conditions describe several presentations characterised by core issues with social affect and stereotyped or repetitive actions. Diagnosis is made by observation and analysis of developmental history. These are heterogeneous conditions which can carry various co-morbidities and whilst described as life-long are affected by age and maturation. Autism means different things to different people. To some it means a need for life-long support. To others it is part of the varied tapestry of humanity. To all it means a need to foster a welcoming society with appropriate support and opportunities.